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Management of cushing’s syndrome in patients with adrenocortical cancer: state of the art and future perspectives
Valentina Guarnotta1D . Antonio Stigliano2D . Massimo Terzolo3(D . Giorgio Arnaldi1D
Accepted: 22 July 2025 / Published online: 30 July 2025 @ The Author(s) 2025
Abstract
Adrenocortical cancers (ACCs) are rare tumours, with up to 50% of cases associated with hypercortisolism. Cortisol- secreting ACCs are characterized by a worse prognosis, and in these patients, the normalization of hypercortisolism is mandatory and requires an urgent approach to avoid complications related to glucocorticoid excess. Clinical and biochemi- cal parameters, including hormonal values, can be used to define cortisol normalization. However, in patients on concomi- tant mitotane treatment, serum cortisol and ACTH levels may be falsely altered and thus unreliable for defining cortisol normalization. Adrenal steroidogenesis inhibitors, alone or in combination, are the first-line treatment for severe hyper- cortisolism in ACC due to their rapid action, efficacy, and safety profile. Mitotane is the cornerstone of ACC treatment in both adjuvant and advanced settings. Similarly, glucocorticoid receptor antagonists also have a rapid onset of action, but their use is limited by challenges in monitoring efficacy and safety. This review aims to address the critical aspects of managing cortisol-secreting ACC, including the definition of hypercortisolism control, current therapeutic approaches and future perspectives for ACC, with a focus to the potential role of immune checkpoint inhibitors.
Keywords Cushing’s syndrome . Adrenocortical carcinoma/cancer . Steroidogenesis inhibitors . Cortisol-secreting . Glucocorticoid excess
| Abbreviations | ||
|---|---|---|
| 2S,4R | Stereoisomer configuration (e.g., of a drug molecule) | |
| ACCs | Adrenocortical carcinomas | |
| ☒ Giorgio Arnaldi | ACTH | Adrenocorticotropic hormone |
| giorgio.arnaldi@unipa.it | APC | Adenomatous polyposis coli |
| Valentina Guarnotta | CBG | Cortisol binding globulin |
| valentina.guarnotta@unipa.it | CPS | Combined Positive Score |
| Antonio Stigliano | CR | Complete response |
| antonio.stigliano@uniroma1.it | CS | Cushing's syndrome |
| Massimo Terzolo | CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
| massimo.terzolo@unito.it | EDP-M | Etoposide, Doxorubicin, Cisplatin plus |
| 1 Unit of Endocrinology, Department of Health Promotion, | Mitotane | |
| Mother and Child Care, Internal Medicine and Medical | EMA | European Medicines Agency |
| Specialties, Policlinico Paolo Giaccone, Università degli studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy | ENSAT | European Network for the Study of Adrenal Tumors |
| EPCAM | Epithelial cell adhesion molecule | |
| 2 Endocrinology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant' Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy | FDA | |
| Food and Drug Administration | ||
| HSD11B2 | 11-Hydroxysteroid dehydrogenase type 2 | |
| ICIs | Immune checkpoint inhibitors | |
| 3 Internal Medicine, Department of Clinical and Biological | IGF2 | Insulin-like growth factor 2 |
| Sciences, S. Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy | K | Potassium |
MEN 1
Multiple endocrine neoplasia type 1
MLH1
MutL homolog 1
MSH2
MutS homolog 2
MSH6
MutS homolog 6
PD Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PMS2
Postmeiotic segregation increased 2
PR
Partial response
PRKAR1A
Protein kinase cAMP-dependent type I regu- latory subunit alpha Patients
Pts
QID
Quarter in die (four times a day)
SD
Stable disease
TID
Ter in die (three times a day)
TP53
Tumor protein p53 gene
TPS
Tumor Proportion Score
UFC
Urinary free cortisol
US
United States
H
Hour
Kg
Kilograms
Mg
Milligrams
q3w
Every 3 weeks (quaque 3 weeks)
S
Seconds
1 Background
Adrenocortical cancer (ACC) is a rare tumour that arises from adrenal cortex. Its incidence is on average 1-2 case per million persons per year and affects more frequently women (55-60% of cases) [1]. The incidence follows a bimodal age distribution, with a first peak in childhood and a second plateau between 40 and 50 years of age. It is generally a sporadic tumour, even though it can be also part of a heredi- tary syndrome including the Li Fraumeni (TP53), multiple endocrine neoplasia type 1 (MEN 1), Lynch syndrome (MSH2, MLH1, PMS2, MSH6, EPCAM), Carney complex (PRKAR1A), type 1 neuro fibromatosis (MEN1), familial adenomatous polyposis coli (APC) and Beckwith-Wiede- man (IGF2 locus) [2].
ACC has a complex pathogenesis due to chromosomal aberrations, epigenetic and genetic mutations [3]. It is an aggressive tumour with a poor 5-year prognosis ranging from 16 to 47%, strongly influenced by age, tumour stage, hormonal hypersecretion, mitotic rate, tumour grade and surgical resection margins [4-6].
ACC can present as a non-functioning tumour showing symptoms as back or abdominal pain, nausea, vomiting, slight fever, weight loss or as a hormone-secreting tumour. Hormonal hypersecretion is very frequent in patients with ACC although the degree of secretion is highly variable
and consequently the clinical consequences are also differ- ent [7, 8]. It is estimated that more than 50% of ACC are hyperfunctioning and among them at least 60% of cases are characterized by cortisol hypersecretion alone or combined with adrenal androgens (25%, mainly testosterone). Rare is aldosterone secretion (7-8%) and extremely rare oestrogen secretion (1-2%) [9].
2 Adrenocortical cancer and severe hypercortisolism: clinical characteristics and prognosis
Cortisol-secreting ACC are characterized by worse progno- sis, higher recurrence rates, and worse survival than non- functioning ACCs [7].
Clinical presentation can be different depending on the degree and the sudden onset of hypercortisolism [7].
In patients with mild hypercortisolism the onset of clini- cal symptoms can be slower than severe hypercortisolism and include facial plethora, easy bruising, weight gain and diabetes mellitus.
In severe hypercortisolism the clinical onset of the dis- ease is very rapid and life-threatening. It can manifest with severe and resistant hypertension often associated with a severe hypokaliemia that frequently requires an immediate hospitalization. Hypokaliemia is generally due to the glu- cocorticoid excess that triggers mineralcorticoid receptors inactivating the capacity of 11beta-hydroxysteroid dehy- drogenase isoenzyme 2 (HSD11B2). ACC patients with severe hypercortisolism can also manifest with deep venous thrombosis, pulmonary embolism, sepsis, acute psychosis and severe hyperglycaemia.
Cortisol hypersecretion is generally viewed as an inde- pendent worse prognostic parameter of ACC [2, 10] and it is generally associated to increased mortality and morbid- ity [11]. Currently, there are few studies which evaluated whether hypercortisolism control is associated to a better overall survival and whether the effects of hypercortisolism control could be attributed to anti-neoplastic therapy [12].
Further, a recent retrospective study showed that 4 out of 74 patients with ACC died before any specific cancer spe- cific treatment for lethal complications of hypercortisolism, but not for tumoral progression [13].
In a multicentric study conducted on 524 patients with ACC (ENSAT stage 1-2-3), hypercortisolism was confirmed to be a negative prognostic factor, in terms of relapse-free survival and overall survival, even though cortisol levels were not associated with mitotic index [5]. This finding could support the hypothesis that in patients with hyper- cortisolism other mechanisms could correlate the cortisol excess with the tumour aggressiveness. Maybe, the decrease
of overall survival in these patients could be attributed to the effects of cortisol excess in increasing mortality, and to the suppressive effects of hypercortisolism on immune system, rather than a direct effect.
According to most recent guidelines the normalization of hormonal excess represents a priority in the management of patients with hormone-secreting ACC and medical therapy is strongly recommended to obtain the hormonal control [14].
Although there are no data on the association between hypercortisolism control and overall survival, it is conceiv- able that the control of thromboembolic, metabolic and car- diovascular risk may be correlated to better outcome.
3 Assessing and monitoring hypercortisolism control during medical therapy in ACC
The clinical and biochemical criteria to define control of hypercortisolism are not different from those used in other forms of Cushing’s syndrome (CS) even though the com- plexity of the clinical picture often requires special consid- erations and precautions [15]. Certainly, patients should be managed in referral centers by physicians with extensive experience, generally defined as the management of at least 5-10 new cases of ACC per year.
The treatment of hypercortisolism is aimed at improving the clinical and biochemical parameters which then allow tumour-directed treatments (surgery or chemotherapy). The same antineoplastic treatment could then influence hor- monal secretion and therefore could contribute to the clini- cal benefit.
There are few studies that have analyzed in detail the effects obtained from the control of hypercortisolism com- pared to therapy aimed at treating the tumor. The use of mitotane does not allow us to distinguish with certainty the two actions given by the mechanism of action of this drug.
Clinical parameters include blood pressure, weight and CS symptoms and signs. A decrease in the number of anti- hypertensive drugs, anti-diabetic agents, weight loss and improvement in phenotypic characteristics are useful mark- ers of hypercortisolism control. Notably, changes in blood pressure are very rapid and for this reason blood pressure lowering can be considered as an early predictor of hyper- cortisolism control. Biochemical parameters include serum potassium level, coagulation parameters and glycaemic val- ues whose changes occur rapidly and are not affected by a potential mitotane therapy.
Further, also hormonal parameters could be evaluated including urinary free cortisol (UFC), early morning serum and salivary cortisol and ACTH, even though in case of
concomitant administration of mitotane, some of these val- ues may be unreliable. Indeed, UFC may be falsely elevated as mitotane alters steroid clearance and increased catabo- lism [16]. Salivary cortisol is not affected by cortisol bind- ing globulin (CBG) alterations and might reflects the free serum cortisol and may enable a more accurate evaluation of cortisol secretion [17]. By contrast, mitotane treatment could affect serum cortisol due to its effect on the increase in CBG and ACTH levels by inhibitory effect. In addition, some steroidogenesis inhibitors, as metyrapone and osilo- drostat, can cause increase in 11-deoxycortisol, which can cross-react in many immunoassays for serum and urinary cortisol, resulting in apparently high cortisol values and potentially masking biochemical hypoadrenalism [18].
In clinical practice, monitoring should be performed at baseline, before starting medical therapy, and then at regu- lar intervals based on the clinical status and pharmacologic treatment used. Initially, assessments every 2-4 weeks may be appropriate to guide dose titration and evaluate early treatment effects. Once a biochemical and clinical response is achieved, the monitoring interval may be extended to every 2-3 months.
Particular attention should be paid to potential rapid changes in blood pressure, glycaemia and potassium lev- els, which may require prompt therapeutic adjustment. Hor- monal parameters (urinary free, serum and salivary cortisol levels) should be interpreted with caution during mitotane treatment. These parameters should ideally be assessed using mass spectrometry, which minimizes cross-reactivity, provides more accurate cortisol measurements, and is less influenced by CBG variations [19].
4 Mitotane, steroidogenesis inhibitors and combined treatment
The drugs, either alone or in combination, are the same as those used in the treatment of severe hypercortisolism [18]. In the case of mild hypercortisolism, however, the use of mitotane alone may be sufficient although its efficacy is often delayed by several days/weeks.
As mentioned, in patients with severe hypercortisolism a rapid control should be obtained. Although surgery rep- resents the treatment of choice, sometimes it cannot be performed immediately. Adrenal directed drugs, steroido- genesis inhibitors, can instead effectively be used to manage rapidly severe hypercortisolism, either as monotherapy or in combination with other drugs including mitotane [14, 20].
Mitotane is the mainstay of treatment of ACC both as adjuvant treatment and in patients not candidates for sur- gery or with metastatic disease. The drug acts primarily on fasciculata and reticularis zonae, less on glomerular of
adrenal gland reducing the glucocorticoids and 17-hydroxy- corticosteroids synthesis, beyond to inhibit the expression of many enzymes involved in steroidogenesis [21]. Further- more, this reduces cellular energy mechanisms by acting on the mitochondrial machinery [22]. For its characteristic mechanism of action, mitotane can be considered both an adrenolytic and a steroidogenesis inhibitor drug ensuring an adequate control of hypercortisolism. However, due to the necessity of attaining therapeutic levels its efficacy is delayed by several weeks with a slow effect. For this reason, mitotane alone is not recommended for the management of severe hypercortisolism, while it should be used for mild hypercortisolism.
Currently, a comparative study of the efficacy of steroido- genesis inhibitors in the management of severe hypercorti- solism in ACC is lacking, while there are studies evaluating the efficacy of single steroidogenesis inhibitors and gluco- corticoid receptor antagonists.
Ketoconazole is an imidazole derivative anti-fungal compound that inhibits adrenal steroidogenesis by acting at several cytochrome P450 steroidogenic enzymes. Adverse events include gastrointestinal symptoms and headache, and in the long-term, irregular menses in females and decreased libido and gynaecomastia in males respectively. In addition, hepatotoxicity could develop. Despite its clinical efficacy, characterized also by a rapid action in controlling severe hypercortisolism [23], it interacts with CYP3A4 that is also the substrate of interaction of mitotane. The mechanism of actions on CYP3A4 of mitotane and ketoconazole are dif- ferent [24]. Indeed, mitotane is a CYP3A4 inducer, while ketoconazole is a CYP3A4 inhibitor. However, in the over- all context it is difficult to predict the effects of their com- bination and a therapeutic drug monitoring should be done in a hospital setting. Ketoconazole should be avoided at the start of mitotane because for the reasons stated above it will be difficult to attribute hepatotoxicity to one or the other drug. It should, however, be noted that for adequate oral absorption, ketoconazole requires an acidic gastric envi- ronment and the suggested dose to treat hypercortisolism is 400-1200 mg/day.
Corcuff et al. reported 22 patients with severe hypercor- tisolism, 14 with ectopic Cushing’s syndrome and 8 with ACC, treated with a combination of ketoconazole and metyrapone [25]. All patients had hypertension, 6 out 8 had hypokalaemia, 3 out 8 had diabetes mellitus. Ketocon- azole was started with a variable dose ranging from 600 to 1200 mg/day, while metyrapone had a starting dose ranging from 750 to 4500 mg/day. In 5 out of 8 patients mitotane was started immediately in combination with metyrapone and ketoconazole. UFC was normalized after 1 week in 5 out 8 patients. After 1 month blood pressure, glycaemia and
potassium values were also improved in the most of patients. Only a patient interrupted ketoconazole due to liver toxicity.
Levoketoconazole is the 2 S,4R stereoisomer of keto- conazole available as an immediate-release tablet contain- ing 150 mg compound. Levoketoconazole inhibits adrenal steroidogenesis more potently than ketoconazole but its hepatic exposure is less extensive. The therapeutic dose is 150-600 mg twice-daily and reduce safety concerns on QT interval prolongation, hepatotoxicity and CYP7A1- mediated drug-drug interactions. FDA recently approved levoketoconazole for the treatment of CS in adults who are not eligible or have failed surgery. However, to our knowl- edge, there are no studies on levoketoconazole treatment of hypercortisolism associated with ACC.
Metyrapone is an 11-beta-hydroxylase inhibitor block- ing the conversion of 11-deoxycortisol in cortisol. This drug is available as an immediate-release capsule containing 250 mg compound, after oral ingestion, is absorbed rapidly but due to its high inter-individual variability in pharmacoki- netics and short half-life it requires four-to-six daily admin- istrations at doses ranging from 500 to 6000 mg/day. It is characterized by a rapid onset, within 24-72 h and high effi- cacy [26]. Its metabolism and elimination are not influenced by mitotane and for this reason the combination of these two drugs can be considered safe [27]. Metyrapone efficacy in severe hypercortisolism is scarcely documented although in ENSAT ACC Guideline [14] this drug was considered the first therapeutic choice for the management of patients with advanced ACC and severe CS. Indeed, there are no studies on severe hypercortisolism treated with metyrapone alone, since in most studies a combination therapy was employed, rather than a monotherapy.
Claps et al. reported 3 male patients with cortisol-secret- ing ACCs, two with a metastatic form and the other one with a locally advanced form [27]. Only one out of 3 had a severe hypercortisolism. Combined chemotherapy, etopo- side + doxorubicin and platinum, mitotane and metyrapone were used. Mitotane was started at dose of 3000 mg/daily and metyrapone at the dose of 750 mg/daily (that corre- sponded at the maximum dose). After 4 weeks of treatment, the patients showed an improvement of clinical condi- tions combined with an increase in potassium value and a decrease in UFC. No significant change in serum cortisol was observed. The control of hypercortisolism was likely due to the synergistic effect of metyrapone and mitotane, which led to a rapid clinical improvement. At 12 weeks one patient had a minimal response and another one had a partial response, while the third patient had a progressive disease.
Osilodrostat is an oral inhibitor of adrenal 11-hydroxylase and aldosterone synthase currently approved by FDA and EMA for the treatment of CS. It is well tolerated. The sug- gested initial dosage is 2 mg twice daily. Up-titration should
be gradual and based on individual response (usually, cor- tisol levels and/or symptoms of adrenal insufficiency) and tolerability. The usual daily maintenance dose was 4-14 mg and the maximum dosage is 30 mg twice daily. Osilodrostat has been demonstrated to be efficacious in obtaining rapid serum cortisol and blood pressure reductions. In 2020, Hais- saguerre et al. reported a case of severe hypercortisolism due to an ACC who interrupted ketoconazole for liver toxic- ity and was treated with the combination of osilodrostat and mitotane obtaining a normalization of cortisol values after 2 weeks [28]. In 2022, Tabarin et al. reported 7 cases of ACC treated with osilodrostat [12]. Mitotane was combined in 3 patients. Two had a previous treatment with metyrapone, which was interrupted due to the lack of efficacy. After two weeks a significant decrease in UFC was observed in 6 out of 7 patients. The mean doses were ranging from 4 to 40 mg/ day, even though only 2 patients were treated with a dose less than 10 mg/day. No treatment escape was observed, even though the mean duration of treatment was quite short (14 weeks). In addition, the treatment was safe and well toler- ated. One patient showed a worsening of hypokaliemia and 3 experienced adrenal insufficiency, which was adequately managed by hydrocortisone replacement therapy.
Etomidate is an anaesthetic agent with sedative-hypnotic activity. It has got also an adrenocortical inhibition action blocking the 110-hydroxylase, CYP17A1 and cholesterol side-chain cleavage enzyme. It is generally used in an emer- gency setting in hospitalized patients, to rapidly treat hyper- cortisolism, due also to its parenteral administration and it is considered an adequate therapy for severe hypercortisolism [29]. Currently, there are only some case reports on the use of etomidate in cortisol-secreting ACC, confirming its suc- cessful effect in rapid normalization of cortisol levels and improvement in blood pressure [30-33]. Due to its charac- teristics, etomidate should be recommended in patients who need to reach a rapid control of hypercortisolism or cannot take oral therapy.
The above-mentioned studies are reported in Table 1.
5 “Block and replace” or “titration-to- normalization” treatment protocols
Generally, there are two treatment strategies based on patients’ clinical picture and biochemical characteristics: the “titration” or “normalization” regimen aims at obtain- ing control of hypercortisolism via gradual dose up-/down- titration, whereas the “block and replace”, which combines higher adrenostatic doses with glucocorticoid replacement.
The “titration to normalization” approach is commonly used in patients with mild or moderate hypercortisolism. It is based on the use of steroidogenesis inhibitors which
could be initiated at low daily doses (e.g., ketoconazole 400-600 mg, metyrapone 500-750 mg, osilodrostat 4 mg, levoketoconazole 300 mg), progressively increased, to reach eucortisolism. This approach is generally slower but avoids adrenal insufficiency and can be effective.
The “block and replace” regimen is used in severe hyper- cortisolism in order to obtain a rapid control of hyper- cortisolism and to avoid an alternation between over and underdosing [34]. However, block and replace regimen is more expensive and requires more tablets per day and a good patient’s compliance. A potential scheme of “block and replace” regimen could involve high doses of steroido- genesis inhibitors as reported by Corcuff et al. who reported mean starting doses of metyrapone of 2125 mg/day and ketoconazole of 900 mg/day [25]. Osilodrostat could be started at a dose of 5-10 mg twice daily to be increased in the following days up to 20-30 mg twice daily [34, 35]. Hydrocortisone could be started at same doses of adrenal insufficiency based on patients weight (0.12 mg/kg) [36] or body surface (10-12 mg/m2 daily) [37] (Fig. 1). However, in patients receiving mitotane, glucocorticoid dose adjust- ments are necessary.
Mitotane-induced CYP3A4 activation leads to rapid inactivation of more than 50% of administered hydrocorti- sone, requiring at least a doubling of the replacement dose to achieve glucocorticoid exposure comparable to that in individuals not receiving CYP3A4-inducing agents [38].
The risk of adrenal insufficiency and side effects (espe- cially gastrointestinal and hepatic) must always be consid- ered, especially when high doses are used. Patients need to be educated about symptoms and signs of adrenal insuffi- ciency. All patients at risk for adrenal insufficiency need to be supplied with emergency medication and instructions.
Metyrapone and osilodrostat can lead to high blood pres- sure, hypokalemia, edema and androgens secondary to the accumulation of precursors with mineralocorticoid activity such as 11-deoxycortisol and 11-deoxycorticosterone.
Hypokalemia depending on its severity, is treated with oral potassium or parenteral administration. Spironolac- tone and other potassium-sparing drugs can be use highly effective, monitoring of serum potassium to the risk of hyperkalemia.
With regard to etomidate, treatment protocols include high-doses (0.5-1 mg/kg/h) which, generally, require com- bined treatment with intravenous hydrocortisone, to avoid adrenal insufficiency, or low-doses (0.04-0.05 mg/kg/h) which induce partial suppression [31, 39].
In emergency settings, an intravenous bolus of 3-5 mg of etomidate administered over 30-60 s followed by infusion rate of 0.02-0.10 mg/kg/h, has been shown to rapidly sup- press cortisol production in most patients [40, 41].
| Authors | Drugs | Patients | Maximum dose | Starting dose | Stage of disease | Time of hyper- cortisolism control | Combina- tion with mitotane | Parameters evaluated to define hypercortisolism control | Replace- ment hydro- cortisone therapy |
|---|---|---|---|---|---|---|---|---|---|
| Claps et al. | Metyrapone | 3 | 750 mg/day | 750 mg/day | 2 pts: IV stage 1 pt: III stage | 4 weeks | Yes | Weight, K, UFC, ACTH, serum cortisol, glucose | No |
| Corcuff et al. | Metyra- pone and | 8 | Ketoconazole 1200 mg/day | Ketoconazole 600-1200 mg/ day | 3 pts: Stage II 5 pts: | 1 week (5/8) 1 months (7/8) | Yes (5/8) | UFC, midnight cortisol, midnight ACTH, blood pressure, K, glucose | Yes (2/8) |
| ketoconazole | Metyrapone 4500 mg/day | Metyrapone 750-4500 mg/ day | Stage IV | ||||||
| Haissaguerre et al. | Osilodrostat | 1 | 44 mg/day | 5 mg/day | NA | 2 weeks | Yes | Serum cortisol | Yes |
| Tabarin et al. | Osilodrostat | 7 | 40 mg/day | 2-20 mg/day | 5pts: Stage IV | 1 week (2/7) | Yes (7/8) | UFC, serum cortisol, K, glu- | Yes (2/7) |
| 1 pt: Stage III 1 pt: Stage II | 1 month (1/7) 2 months (2/7) 3 months (2/7) | cose, blood pressure, phenotypic characteristics | |||||||
| Łebek- Szatańska et al. | Etomidate + ketoconazole | 1 | 5 mg/h | 2.5 mg at bolus and an infusion of 0.01-0.02 mg/ kg/h (1-2 mg/h) etomi- date + 1200 mg/day ketoconazole | Stage IV | 4 days | No | Serum cortisol, glucose, K, blood pressure | Yes |
| Wan Muhamad Hatta et al. | Etomidate | 1 | 42.8 mcg/kg/h | 42.8 mcg/kg/h | Stage IV | 7 days | Yes | Serum cortisol | No |
| Huang CJ et al. | Etomidate | 1 | 2 mg/h | 2 mg/h continuous infusion | Stage IV | 2 days | No | Serum cortisol | No |
| Castinetti et al. | Mifepristone | 12 | 2000 mg/day | 400-1000 mg/day | Stage IV | 1-6 months | Yes | Blood pressure, clinical signs, K, | Yes (2/12) |
Abbreviations: pts: patients; UFC urinary free cortisol; K potassium
| Ketoconazole | Metyrapone | Osilodrostat | Etomidate | |
|---|---|---|---|---|
| Day 1 | 200 mg TID | 500 mg TID | 5-10 mg TID ** | 0.1-0.3 mg/kg/h |
| Day 5 | 400 mg TID | 1000 mg TID | 15-20 mg TID ** | |
| Day 7 onwards | 400 mg TID | 1000 mg QID | 20-30 mg TID ** |
| REPLACEMENT GLUCOCORTICOID THERAPY | ||||
|---|---|---|---|---|
| Hydrocortisone | Dexamethasone | Prednisone/Prednisolone | ||
| Starting doses | 20-30 mg | 0.25-0.5 mg once a day | 3-7.5 mg once a day | |
| twice/thrice a day | ||||
| Adjustment with concomitant mitotane | 40-60 mg twice/thrice a day | 0.5-1 mg once a day | 6-15 mg once a day | |
| Adverse events | Monitoring | Practical management | ||||
|---|---|---|---|---|---|---|
| Mitotane | Gastrointestinal disturbances, adrenal insufficiency, increase in hepatic enzymes, hyperlipidemia, neurotoxicity, gynecomastia, thyroid disorders | Blood count and liver test after 3-4 weeks, then every 3 months; TSH, FT4, HDL, LDL cholesterol, testosterone and SHBG. | Start bridging therapy with glucocorticoids. Use antiemetic and anti-diarrheal medication for GI disturbances. If severe GI, neurotoxic symptoms or transaminases >5 fold stop mitotane. Consider replacement therapy for hypothyroidism and hypogonadism and statins for hypercholesterolemia. | |||
| Ketoconazole | Hepatotoxicity, gastrointestinal disturbances, adrenalinsufficiency, skin rash, hypogonadism and gynecomastia in men. | Test liver enzymes weekly at start. Monitor androgens and ECG for QT prolongation. Check drug interactions. | Stop immediately if ALT/AST >5x ULN. | |||
| Levoketoconazole | Nausea, headache, adrenal insufficiency, increase in liver enzymes | Monitor ECG for QT. Check ALT monthly. No data in ACC. Start with lowest dose. | Decrease/interrupt drug for ALT and/or AST >5x ULN | |||
| Metyrapone | Nausea, hypertension, hypokalemia, edema, acne, hirsutism, fatigue, dizziness, adrenalinsufficiency | Electrolytes, blood pressure during the first 15 days and at each dose change and every 2-3 months. Monitor ECG for QT prolongation. | Add aldosterone receptor antagonists if hypertension and/or hypokalemia occur. Consider supplementation of potassium. Reduce or interrupt the drug if severe adverse events | |||
| Osilodrostat | Fatigue, nausea, headache, diarrhea, and adrenal insufficiency. Hypokaliemia and hypertension. | Monitor electrolytes, blood pressure after starting treatment, at each dose change and every 2-3 months. Monitor ECG for QT prolongation. | Use hydrocortisone and reduce/interrupt osilodrostat if symptoms of adrenal insufficiency occur. Use supplementation of potassium and/or aldosterone receptor antagonists for hypokaliemia and for hypertension. | |||
| Etomidate | Sedation, nausea, bradycardia, hypotension, adrenal suppression. | Use only in hospital setting. Careful monitoring of clinical symptoms and electrolytes, blood pressure. | Titrate slowly with cortisol monitoring every 6-12h. Support blood pressure if needed. | |||
The management of cortisol-lowering treatment adverse events is reported in Figs. 2 and 3.
6 Glucocorticoid receptor antagonists
Mifepristone is a glucocorticoid receptor antagonist with an 18-fold higher affinity to the glucocorticoid receptor than cortisol, with anti-androgen and anti-progestin effects.
Mifepristone is approved by the US FDA for the treatment of hyperglycemia secondary to CS in patients with disease recurrence or when they are not amenable to surgery. It is characterized by rapid action and efficacy in severe hyper- cortisolism. However, due to its mechanism of action, its efficacy can be monitored only by glucose, weight and blood pressure values. Potassium should be monitored due to the risk of adrenal insufficiency. Castinetti et al. reported 11 patients with ACC and hypercortisolism who were
Serum mitotane levels:
Monitor serum potassium and sodium periodically, as hypokalemia is common notably with metyrapone and osilodrostat and mineralocorticoid deficiency can occur especially with mitotane. Supplement and/or use mineralocorticoid replacement as needed.
For mitotane, measure plasma levels every 4-6 weeks until steady state, then every 2-3 months. Dose adjustments should be based on both clinical response and serum levels, as mitotane has a long half-life and delayed onset.
Electrolytes
Liver function tests (LFTs) Monitor LFTs at baseline and regularly during therapy, especially with ketoconazole, levoketoconazole and mitotane, due to risk of hepatotoxicity. Reduce the dose if moderate hepatotoxicity occurs. Interrupt or discontinue therapy if liver enzymes ≥ 3ULN.
Electrocardiogram (ECG) Obtain baseline and periodic ECGs to monitor QT interval, particularly with ketoconazole, which can prolong QT. Correct hypokalemia and avoid other QT-prolonging drugs.
Adrenal insufficiency Assess for clinical signs and symptoms (hypotension, hyponatremia, hyperkalemia, fatigue, nausea). Glucocorticoid replacement is often required, and higher doses may be needed due to increased metabolism with mitotane.
Patient with Cushing’s syndrome and ACC on cortisol-lowering treatment
Additional safety and efficacy parameters
Monitor for dyslipidemia, hypothyroidism, and reproductive dysfunction with mitotane. Assess for neurologic side effects at higher mitotane levels. Periodically evaluate for clinical improvement in hypercortisolism and adjust therapy accordingly.
previously treated with other therapies including surgery, chemotherapy and mitotane [42]. Eight patients had also a previous treatment with other anti-cortisol drugs (ketocon- azole, metyrapone and etomidate). In eight patients there was an improvement in hypercortisolism signs within the first month. The median dose was 400 mg/day (200-1000 mg/ day) and a median duration of treatment of 2 months (5 days to 6 months). Mifepristone was associated with improve- ment of psychiatric symptoms, blood pressure and diabetes mellitus, while hypokalaemia was worsened. In 8 patients a tumour progression was observed and 3 stopped the treat- ment for lack of efficacy and hypokalaemia worsening. In the end 2 patients experienced adrenal insufficiency.
6.1 Future directions
Relacorilant is a highly selective glucocorticoid modula- tor, that competitively antagonizes cortisol activity, without anti-progestin effects. It is an investigational product and it has not yet been approved for the treatment of CS, although it has demonstrated promising results (patients with ACC were excluded in this study) [43]. Currently, due to the nov- elty of this drug, only a clinical trial has been performed on its use in ACC. This trial evaluated the effects of com- bination of relacorilant and pembrolizumab on advanced ACC and hypercortisolism both on tumoral progression and
on hypercortisolism control. The results of this interesting study are expected soon (NCT04373265, www.clinicaltri- als.gov). Relacorilant might increase the recruitment and function of natural killer and other immune cells in the tumor microenvironment, promoting immune response in ACC expressing glucocorticoid receptors.
7 Immune checkpoint inhibitors and their role in cortisol-secreting ACCs
Immune checkpoint inhibitors (ICIs), such as PD-1, PD-L1, and CTLA-4 blockers, have changed cancer therapy by modulating T-cell inhibitory pathways and enhancing anti- tumor immunity. Initially approved for malignancies like melanoma, renal cell carcinoma, and non-small-cell lung cancer, ICIs have more recently been investigated in ACC, because PD-L1 expression has been detected on both tumor and infiltrating immune cells [44]. A study analyzing 162 tumor samples from 122 ACC patients revealed that PD-1 was expressed in 26.5%, PD-L1 in 24.7%, and CTLA-4 in 52.5% of cases. Among these, only PD-1 expression was associated with longer progression-free survival [45].
Only a few studies provided data on hormone-secret- ing ACCs (Table 2). However, cortisol excess may impair immunotherapy efficacy, given that high glucocorticoid
| Authors | Study | Year | Therapy | PDL1-PD1 expression | Patients with cortisol-secreting ACC/Total number of patients | Adrenal insufficiency | Hypercorti- solism Control | Combination with mitotane | Tumoral Response |
|---|---|---|---|---|---|---|---|---|---|
| Casey et al. | Case report | 2018 | Pembrolizumab + mitotane followed by | <1% | 1 | Unknown | Not reported | Yes | PD |
| Pembrolizumab + metirapone | |||||||||
| Carneiro et al. | Multicentric | 2019 | Nivolumab | 6/10 | 2/10 | 1 patient with non- functioning ACC | Not reported | Yes | PD in both patients |
| Habra et al. | Monocentric | 2019 | Pembrolizumab | 0/14 | 7/16 | No | Not reported | No | 1 PR |
| Phase 2 | 3 SD | ||||||||
| 3 PD | |||||||||
| Head et al. | Retrospective | 2019 | Pembrolizumab + mitotane | Not reported | 3/6 | No | Not reported | Yes | 3 SD |
| Bedrose et al. | Retrospective case | 2020 | Lenvatinib and pembrolizumab | Not reported | 3/8 | No | Not reported | No | 2 PD |
| series | 1 SD | ||||||||
| Klein et al. | Multicentric open | 2021 | Nivolumab and ipilimumab for 4 | Negative | 2/6 | 1 patient with | Not reported | No | 1 SD |
| label phase 2 | doses and after nivolumab | cortisol-secreting ACC and 1 patient with non-function- ing ACC | 1 PR | ||||||
| Remde et al. | Multicentric | 2023 | Pembrolizumab (n=32) | Positive | 22/54 | No | Not reported | No | 4/22 PR (2 |
| Retrospective | Nivolumab (n=13) | nivolumab, | |||||||
| Avelumab (n=6) | 1 avelumab, | ||||||||
| Atezolizumab (n=1) Ipililumab-nivolumab (n=2) | 1 pembroli- zumab) | ||||||||
| Weng et al. | Case report | 2023 | Sintilimab + etoposide/ paraplatin + mitotane | 0 | 1 | Yes | Not reported | Yes | PR |
| Schwarzlmuel- | Case series | 2024 | Pembrolizumab | 1 patient: TPS | 3 | No | Not reported | No | 1 CR |
| ler et al. | 1%, IC score | 2 PR |
0%, CPS 1
2 patient: no
expression
Abbreviations: ACC adrenocortical cancer; PD progressive disease, PR partial response; SD stable disease; CR: complete response
exposure (≥10 mg prednisone equivalent) is associated with worse outcomes during PD-L1 blockade [46]. Despite the presence of cortisol excess, several studies have reported responses to ICIs in metastatic ACC patients.
Habra et al. observed 1 partial response and 3 stable dis- eases among 7 cortisol-secreting ACC patients treated with pembrolizumab, without any cases of adrenal insufficiency [47]. Similarly, Head et al. reported initial stability followed by progression in 3 cortisol-secreting ACC patients treated with pembrolizumab and mitotane [48]
Remde et al. found partial responses in 4 out of 22 cortisol-secreting ACC patients treated with various ICIs, although progression was common and data on hypercorti- solism control were lacking [49]
Carneiro et al. reported progression in 2 cortisol-secret- ing ACC patients treated with nivolumab [50]. Interestingly, Bedrose et al. showed that 2 out of 3 cortisol-secreting ACC patients treated with pembrolizumab and lenvatinib, without concomitant mitotane, experienced progressive disease with short progression free survival, while the other had a stable disease [51]. Klein et al. showed that 1 cortisol-secreting ACC patient responded with a partial and complete meta- bolic response (the patient developed an adrenalitis), while the other had stable disease to nivolumab and ipilimumab [52]
In addition, some single clinical cases and case series on cortisol secreting ACCs have been reported. Casey et al. reported a patient treated with pembrolizumab stopped after 2 weeks due to the liver failure onset [53]. Weng et al. reported one patient treated with sintilimab and chemo- therapy (etoposide combined to carboplatin) and mitotane obtaining a long-term stable disease [54]. Schwarzlmueller et al. reported 3 female patients with combined androgen and glucocorticoid hypersecretion ACC syndrome, treated with adrenal surgery, EDP-M, brachytherapy and radiation therapy for distant metastases [55]. Due to the progression of disease, patients were treated with pembrolizumab, at the dose of 200 mg q3w, for 23,15 and 10 cycles, obtaining a complete and a partial remission (2 patients), respectively
The aforementioned studies predominantly address tumoural response while providing limited insights into the management of hypercortisolism. Interestingly, three patients, two with non-functioning ACC and one with cortisol-secreting ACC, treated with nivolumab developed adrenal insufficiency, highlighting a potential impact of this drug on adrenal steroidogenesis. Carneiro et al. reported the case of a patient who developed adrenal insufficiency 18 months after discontinuing high-dose steroid therapy, which had been administered to manage transaminase rise as an adverse effect nivolumab-related, suggesting that this con- dition may have been mediated by a robust inflammatory response as well as an antitumour effect [50]
Klein at al. reported two patients who developed adrenal insufficiency, one with non-functioning and one with corti- sol-secreting ACC, both concurrently treated with mitotane. Interestingly, these two patients were the only responding patients [52]
8 Conclusions
Cortisol-secreting ACCs remain a therapeutic challenge for clinicians [55]. They show high aggressiveness and worse prognosis. A rapid control of hypercortisolism should be obtained in all patients to limit the acute complications of glucocorticoid excess. Clinical and biochemical param- eters can be used to define hypercortisolism control includ- ing blood pressure, weight and clinical picture, potassium, glucose level and coagulation parameters (Fig. 4). Caution should be used for serum, urinary and salivary cortisol determination, because these values could be falsely altered by potential mitotane combined treatment
The therapeutic approach to severe hypercortisolism in ACC involves the use of steroidogenesis inhibitors or glucocorticoid receptor antagonists in combination with mitotane. Drug regimens are highly variable, particularly for metyrapone and ketoconazole, with reported mean doses ranging widely depending on clinical severity and individual response. Metyrapone is highly effective, espe- cially when combined with ketoconazole. Osilodrostat has demonstrated a rapid onset of action, sustained hypocorti- solemic effect, and notable efficacy even in cases of severe hypercortisolism.
Cortisol excess has a potential negative impact on immu- notherapy efficacy in cortisol-secreting ACC, with only few patients still respond to ICIs. The management of hypercor- tisolism during ICI therapy remains insufficiently addressed and needs of further research.
Currently there are no evident correlations between hypercortisolism control and improved overall survival in ACC. It may be hypothesized that higher mortality in patients with cortisol-secreting ACCs could be secondary to the detrimental systemic effects of glucocorticoid excess, even though evidence from basic studies suggests that cor- tisol secretion correlates with a more aggressive molecular signature [56]. Therefore, a rapid and sustained control of hypercortisolism in patients with cortisol-secreting ACCs could improve the high risk of mortality, which is due to both to the tumour and to the effects of cortisol itself.
There is a pressing need for cohort and prospective stud- ies that focus on the effects of rapidly controlling hyper- cortisolism on the prognosis of patients with ACC. These studies could offer valuable insights into whether early intervention can significantly improve long-term outcomes
Principal parameters to define clinical and biochemical control of hypercortisolism
Drugs to control hypercortisolism
Weight
Mitotane
Ketoconazole
Blood pressure
Consider
Levoketoconazole
Titration to normalization
Glucose
Metirapone
OR
Osilodrostat
Coagulation, potassium, hormones
Block and replace
Etomidate
Phenotype (facial rubor)
Glucocorticoid receptor antagonists
Immunotherapy (?)
for these patients. Additionally, further research should explore the differences in overall survival rates between individuals with mild and severe hypercortisolism, as these distinctions may help guide treatment strategies and better tailor interventions to the specific needs of patients.
Author contributions V.G., A.S., M.T. and G.A. wrote the main manu- script. V.G., A.S., M.T and G.A. prepared figures. All authors reviewed the manuscript.
Funding Open access funding provided by Università degli Studi di Palermo within the CRUI-CARE Agreement. The authors did not re- ceive support from any organization for the submitted work.
Data availability No datasets were generated or analysed during the current study.
Declarations
Competing interests The authors declare no competing interests.
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References
1. Libé R, Huillard O. Adrenocortical carcinoma: diagnosis, prog- nostic classification and treatment of localized and advanced dis- ease. Cancer Treat Res Commun. 2023;37:100759.
2. Else T, Williams AR, Sabolch A, Jolly S, Miller BS, Hammer GD. Adjuvant therapies and patient and tumor characteristics associ- ated with survival of adult patients with adrenocortical carci- noma. J Clin Endocrinol Metabolism. 2014;99:455-61.
3. Mete O, Erickson LA, Juhlin CC, De Krijger RR, Sasano H, Volante M, et al. Overview of the 2022 WHO classification of adrenal cortical tumors. Endocr Pathol. 2022;33:155-96.
4. Libé R, Borget I, Ronchi CL, Zaggia B, Kroiss M, Kerkhofs T, et al. Prognostic factors in stage III-IV adrenocortical carcino- mas (ACC): an European network for the study of adrenal tumor (ENSAT) study. Ann Oncol. 2015;26:2119-25.
5. Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, et al. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014;65:832-8.
6. Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, et al. Clinical and biological features in the prognosis of adreno- cortical cancer: poor outcome of Cortisol-Secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metabolism. 2006;91:2650-5.
7. Puglisi S, Calabrese A, Ferraù F, Violi MA, Laganà M, Grisanti S, et al. New findings on presentation and outcome of patients with adrenocortical cancer: results from a National cohort study. J Clin Endocrinol Metabolism. 2023;108:2517-25.
8. . Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocor- tical carcinoma with hypercortisolism. Endocrinol Metab Clin North Am. 2018;47:395-407.
9. Seccia TM, Fassina A, Nussdorfer GG, Pessina AC, Rossi GP. Aldosterone-producing adrenocortical carcinoma: an unusual cause of conn’s syndrome with an ominous clinical course. Endocr Relat Cancer. 2005;12:149-59.
10. Ayala-Ramirez M, Jasim S, Feng L, Ejaz S, Deniz F, Busaidy N, et al. Adrenocortical carcinoma: clinical outcomes and prog- nosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013;169:891-9.
11. Braun LT, Vogel F, Reincke M. Long-term morbidity and mortal- ity in patients with Cushing’s syndrome. J Neuroendocrinology [Internet]. 2022 [cited 2023 Feb 22];34. Available from: https://o nlinelibrary.wiley.com/doi/https://doi.org/10.1111/jne.13113
12. Tabarin A, Haissaguerre M, Lassole H, Jannin A, Paepegaey A-C, Chabre O, et al. Efficacy and tolerance of Osilodrostat in patients with cushing’s syndrome due to adrenocortical carcinomas. Eur J Endocrinol. 2022;186:K1-4.
13. Tőke J, Uhlyarik A, Lohinszky J, Stark J, Huszty G, Micsik T, et al. Prognostic factors and mitotane treatment of adrenocorti- cal cancer. Two decades of experience from an institutional case series. Front Endocrinol. 2022;13:952418.
14. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, De Kri- jger RR, et al. European society of endocrinology clinical prac- tice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European network for the study of adrenal tumors. Eur J Endocrinol. 2018;179:G1-46.
15. Fassnacht M, Puglisi S, Kimpel O, Terzolo M. Adrenocorti- cal carcinoma: a practical guide for clinicians. Lancet Diabetes Endocrinol. 2025;13:438-52.
16. Bledsoe T, Island DP, Ney RL, Liddle GW. An effect of o,p’-DDD on the Extra-adrenal metabolism of cortisol in man. J Clin Endo- crinol Metabolism. 1964;24:1303-11.
17. Carrozza C, Lapolla R, Gervasoni J, Rota CA, Locantore P, Pon- tecorvi A, et al. Assessment of salivary free cortisol levels by liquid chromatography with tandem mass spectrometry (LC-MS/ MS) in patients treated with mitotane. HJ. 2012;11:344-9.
18. Marques JVO, Boguszewski CL. Medical therapy in severe hypercortisolism. Best Pract Res Clin Endocrinol Metab. 2021;35:101487.
19. Ceccato F, Barbot M, Zilio M, Frigo AC, Albiger N, Camozzi V, et al. Screening tests for cushing’s syndrome: urinary free corti- sol role measured by LC-MS/MS. J Clin Endocrinol Metabolism. 2015;100:3856-61.
20. Kamenický P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier J-F, et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-Dependent cushing’s syndrome. J Clin Endocrinol Metabolism. 2011;96:2796-804.
21. Paragliola RM, Torino F, Papi G, Locantore P, Pontecorvi A. Role of mitotane in adrenocortical Carcinoma - Review and state of the Art. Eur Endocrinol. 2018;14:62.
22. Hescot S, Slama A, Lombès A, Paci A, Remy H, Leboulleux S, et al. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells. Endocrine-related Cancer. 2013;20:371-81.
23. Ollivier M, Haissaguerre M, Ferriere A, Tabarin A. Should we avoid using ketoconazole in patients with severe cushing’s syn- drome and increased levels of liver enzymes? Eur J Endocrinol. 2018;179:L1-2.
24. Kroiss M, Quinkler M, Lutz WK, Allolio B, Fassnacht M. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma: CYP3A4 induction by mitotane. Clin Endocrinol. 2011;75:585-91.
25. Corcuff J-B, Young J, Masquefa-Giraud P, Chanson P, Bau- din E, Tabarin A. Rapid control of severe neoplastic hypercor- tisolism with Metyrapone and ketoconazole. Eur J Endocrinol. 2015;172:473-81.
26. Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, et al. Effectiveness of Metyrapone in treating cushing’s syndrome: A retrospective multicenter study in 195 patients. J Clin Endocrinol Metabolism. 2015;100:4146-54.
27. Claps M, Cerri S, Grisanti S, Lazzari B, Ferrari V, Roca E, et al. Adding Metyrapone to chemotherapy plus mitotane for cushing’s syndrome due to advanced adrenocortical carcinoma. Endocrine. 2018;61:169-72.
28. Haissaguerre M, Puerto M, Nunes M-L, Tabarin A. Efficacy and tolerance of Osilodrostat in patients with severe cush- ing’s syndrome due to non-pituitary cancers. Eur J Endocrinol. 2020;183:L7-9.
29. Constantinescu SM, Driessens N, Lefebvre A, Furnica RM, Cor- vilain B, Maiter D. Etomidate infusion at low doses is an effective and safe treatment for severe cushing’s syndrome outside inten- sive care. Eur J Endocrinol. 2020;183:161-7.
30. Wan Muhamad Hatta SF, Daly R, Chacko C, Raghavan R. A case of etomidate use in management of adrenocortical carcinoma with hypercortisolemia. J Endocrinol Metab. 2020;10:190-4.
31. Łebek-Szatańska A, Nowak KM, Zgliczyński W, Baum E, Żyłka A, Papierska L. Low-dose etomidate for the management of severe hypercortisolaemia in different clinical scenarios: a case series and review of the literature. Therapeutic Adv Endocrinol. 2019;10:204201881982554.
32. Kwon A, Choi Y, Jung JW, Suh J, Kim H-S. Using etomidate in a Two-month-old infant with Cushing syndrome due to adrenocor- tical carcinoma. Jcrpe. 2022;14:102-6.
33. Hahner S, Stürmer A, Fassnacht M, Hartmann RW, Schewe K, Cochran S, et al. Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines. Horm Metab Res. 2010;42:528-34.
34. Castinetti F, Nieman LK, Reincke M, Newell-Price J. Approach to the patient treated with steroidogenesis inhibitors. J Clin Endo- crinol Metabolism. 2021;106:2114-23.
35. Dzialach L, Sobolewska J, Respondek W, Wojciechowska-Luz- niak A, Kuca P, Witek P. Is there still a place for etomidate in the management of Cushing’s syndrome? The experience of a single center of low-dose etomidate and combined etomidate-osilodro- stat treatment in severe hypercortisolemia. Endocrine [Internet]. 2024 [cited 2025 Jan 31]; Available from: https://link.springer.co m/https://doi.org/10.1007/s12020-024-04135-1
36. Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, et al. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol. 2004;61:367-75.
37. Störmann S, Schopohl J. New and emerging drug therapies for cushing’s disease. Expert Opin Pharmacother. 2018;19:1187-200.
38. Chortis V, Taylor AE, Schneider P, Tomlinson JW, Hughes BA, O’Neil DM, et al. Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5a-Reductase, explaining the need for personalized glucocorticoid and androgen replacement. J Clin Endocrinol Metabolism. 2013;98:161-71.
39. Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of cushing’s disease: a guideline update. Lancet Diabetes Endocri- nol. 2021;9:847-75.
40. Carroll TB, Peppard WJ, Herrmann DJ, Javorsky BR, Wang TS, Patel H, et al. Continuous etomidate infusion for the management of severe Cushing syndrome: validation of a standard protocol. J Endocr Soc. 2019;3:1-12.
41. Nieman LK, Biller BMK, Findling JW, Murad MH, Newell- Price J, Savage MO, et al. Treatment of cushing’s syndrome: an
endocrine society clinical practice guideline. J Clin Endocrinol Metabolism. 2015;100:2807-31.
42. Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, et al. Merits and pitfalls of mifepristone in cushing’s syndrome. Eur J Endocrinol. 2009;160:1003-10.
43. Pivonello R, Bancos I, Feelders RA, Kargi AY, Kerr JM, Gordon MB, et al. Relacorilant, a selective glucocorticoid receptor mod- ulator, induces clinical improvements in patients with Cushing syndrome: results from A prospective, Open-Label phase 2 study. Front Endocrinol. 2021;12:662865.
44. Fay AP, Signoretti S, Callea M, Teló GH, Mckay RR, Song J, et al. Programmed death ligand-1 expression in adrenocortical car- cinoma: an exploratory biomarker study. J Immunotherapy Can- cer. 2015;3:3.
45. Landwehr L-S, Altieri B, Sbiera I, Remde H, Kircher S, Olabe J, et al. Expression and prognostic relevance of PD-1, PD-L1, and CTLA-4 immune checkpoints in adrenocortical carcinoma. J Clin Endocrinol Metabolism. 2024;109:2325-34.
46. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell Death-1 and programmed Death-Ligand 1 Blockade in patients with Non-Small-Cell lung cancer. JCO. 2018;36:2872-8.
47. Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunotherapy Cancer. 2019;7:253.
48. Head L, Kiseljak-Vassiliades K, Clark TJ, Somerset H, King J, Raeburn C, et al. Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. J Endocr Soc. 2019;3:2295-304.
49. Remde H, Schmidt-Pennington L, Reuter M, Landwehr L-S, Jen- sen M, Lahner H, et al. Outcome of immunotherapy in adrenocor- tical carcinoma: a retrospective cohort study. Eur J Endocrinol. 2023;188:485-93.
50. Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gur- sel DB, et al. Nivolumab in metastatic adrenocortical carci- noma: results of a phase 2 trial. J Clin Endocrinol Metabolism. 2019;104:6193-200.
51. Bedrose S, Miller KC, Altameemi L, Ali MS, Nassar S, Garg N, et al. Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. J Immunother Cancer. 2020;8:e001009.
52. Klein O, Senko C, Carlino MS, Markman B, Jackett L, Gao B, et al. Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. OncoImmunology. 2021;10:1908771.
53. Casey RT, Giger O, Seetho I, Marker A, Pitfield D, Boyle LH, et al. Rapid disease progression in a patient with mismatch repair- deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab. Semin Oncol. 2018;45:151-5.
54. Weng Y, Wang L, Wang X-Y, Fan X-X, Yan L, Li Z-H, et al. Case report: remarkable response to a novel combination of mitotane, etoposide, paraplatin, and sintilimab in a patient with metastatic adrenocortical carcinoma. Front Endocrinol. 2023;14:1115893.
55. Schwarzlmueller P, Corradini S, Seidensticker M, Zimmermann P, Schreiner J, Maier T, et al. High-Dose rate brachytherapy com- bined with PD-1 Blockade as a treatment for metastatic adreno- cortical Carcinoma - A single center case series. Horm Metab Res. 2024;56:30-7.
56. Calabrese A, Basile V, Puglisi S, Perotti P, Pia A, Saba L, et al. Adjuvant mitotane therapy is beneficial in non-metastatic adreno- cortical carcinoma at high risk of recurrence. Eur J Endocrinol. 2019;180:387-96.
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